Epidermodysplasia Verruciformis: Tree-Man Disease
EV Overview Epidermodysplasia Verruciformis (EV) is a rare genetic disease that causes an increased risk of HPV infections and cutaneous squamous cell carcinomas. It is considered a genodermatosis, an inherited skin condition, and is an autosomal recessive trait in which some patients have acquired it through X-linked inheritance. The susceptibility to different strains of HPV that results in chronic HPV infection causes grotesque skin abnormalities that include flat, wart-like lesions and hypopigmented macules on multiple anatomical sites. Verrucous lesions are contagious and painful warts that the patient will typically develop at anatomical sites such as the trunk, extremities, and unfortunately the face. This disorder is responsible for causing reddish-brown plaques and nodules that can potentially become carcinomas once the patient reaches 20-40 years old. These are squamous cell carcinomas that are invasive and can disseminate throughout the body. Diagnosing this disorder is not difficult due to the characteristic smoky or light-blue cytoplasm of the cells of the upper epidermis. The lesions generally grow in sun exposed locations of the body and are unresponsive to therapy. There are over 30 identified strains of HPV that are called Epidermodysplasia Verruciformis-Associated HPV's (EV-HPV's), but HPV-5 and HPV-8 are found in more than 90% of patients with squamous cell carcinoma. The nickname "tree-man" comes from the severe cases of Epidermodysplasia Verruciformis in which there is excessive papule growth that join together, form plaques, and if they are left untreated, continue to grow. These growths are malignant transformations of keratinocytes within the skin lesions. Excessive keratin is produced and as seen in Figure 1, the growths will grow to a point where it prevents an individual from doing daily tasks. Genetics Although HPV infections and squamous cell carcinomas are the physical identifiers of this disorder, the Epidermodysplasia Verruciformis gene locus was found to be on chromosome 2p21 to 2p24 as well as chromosome 17q25. However, the mutations that occur are in the EVER1 and EVER2 genes which are located at chromosome position 17q25. With regard to the human genome, they are very close together as the only fall 4,732 base pairs away from each other. In a study called "A homozygous nonsense mutation in the EVER2 gene leads to Epidermodysplasia Verruciformis" (referenced below), researchers used PCR amplification for EVER1 and EVER2 on 50 healthy individuals and 1 individual with Epidermodysplasia Verruciformis. There are 19 exons with EVER1 and 15 exons with EVER2, however, only on exon 6 of the EVER2 gene did PCR provide enticing evidence. A nonsense mutation changed the amino acid coding from Arginine to a stop signal at the 568th base pair position. This premature stop signal terminated the protein 537 amino acids before the real stop codon. Because of this non-functional protein, the patient does not have to ability to control oncogenic HPV infections. Complexes of EVER proteins and zinc transport proteins are known to affect the ability of EV-HPV expression. This concludes that this disorder is due to a mutation and is not a simple polymorphism with minimal effect, as the mutation causes an inability to stop HPV expression. The EVER genes amplified through PCR are a part of the Transmembrane Channel-like (TMC) gene (EVER1/TMC6, EVER2/TMC8), which are localized at the endoplasmic reticulum. The tumors that form from Epidermodysplasia Verruciformis produce transcripts labeled E6 and E7, which are oncogenes that make oncoproteins from HPV infections. When E6 and E7 are expressed, programmed cell death does not occur and keratinocytes become malignant. Interestingly enough E6 and E7 have an effect on the "guardian of the genome," p53. Conclusion Roughly 25% of people with Epidermodysplasia Verruciformis do not have mutations in EVER1 or EVER2. Epidermodysplasia Verruciformis can be contracted by people that have suppressed immune systems, such as HIV or transplant patients. Although malignancies are slow to progress, the conversion process is sped up by UV-light exposure as well as radiographic imaging such as X-rays. Unfortunately the treatments available such as surgical removal or topical agents are are either ineffective or only present temporary improvements. One of the greatest issues surrounding the treatments methods is that fact that there are so many strains of HPV that causes major problems with eradication. The best thing that people with Epidermodysplasia Verruciformis can do is limit the amount of sun exposure they have in order to slow down the progression of the disease. References 1. A homozygous nonsense mutation in the EVER2 gene leads to Epidermodysplasia Verruciformis (Wiley Library) 2. Epidermodysplasia Verruciformis (Medscape) 3. Epidermodysplasia Verruciformis: An early and unusual presentation (NCBI, PMCID: PMC2851455) 4. Epidermodysplasia Verruciformis; EV (OMIM, #226400)